The present invention is concerned with treatment of sleep disorders by administering a cholinesterase inhibitor. In particular, cholinesterase inhibitors that are active at nicotinic receptors and that are selective for acetylcholinesterase over butylcholinesterase are used in treating sleep disorders.
Galantamine (structure immediately below), a tertiary alkaloid, has been isolated from the bulbs of the Caucasian snowdrops Galanthus woronowi (Proskurnina, N. F. and Yakoleva, A. P. 1952, Alkaloids of Galanthus woronowi. II. Isolation of a new alkaloid. (In Russian.) Zh. Obschchei Khim. (J. Gen. Chem.) 22, 1899-1902). It has also been isolated from the common snowdrop Galanthus nivalis (Boit, 1954).

The chemical name of galantamine is [4aS-(4aα,6β,8aR*)]-4a,5,9,10 11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol; both the base compound and its hydrobromide are laevorotatory. Galantamine is a well-known acetylcholinesterase inhibitor which is active at nicotinic receptor sites but not on muscarinic receptor sites. It is capable of passing the blood-brain barrier in humans, and presents no severe side effects in therapeutically effective dosages.
Acetylcholine is known to play a role in sleep and may have a more specific role in the regulation of REM sleep. (Shiromani et al. Annu. Rev Pharmacol Toxicol. 1987; 27:137-56) Furthermore, based on the dense cholinergic innervation of the basal forebrain, acetylcholine is thought to also play a role in sleep onset and maintenance (Donnet A, Encephale. 1993 May-June; 19(3):237-40.). Effects of acetylcholine on sleep can be seen under conditions of acetylcholine deficiency such as Alzheimer's disease or under conditions of cholinergic stimulation as after exposure to nicotine.
Dyssomnias are chronic disorders of sleep usually associated with excess sleepiness or complaints of insomnia. While some of these dyssomnias may be attributable to circadian disruptions (eg. jet-lag or shift work), others are due to instrinsic disorders related to the ability to fall asleep, remain asleep or arise from sleep without a precipitating event. Other forms of dyssomnias are related to external factors interfering with sleep (i.e. noise, hypnotic dependence, altitude) (International Classification of Sleep Disorders, 1990).
One of the cardinal features of restorative sleep is the need for the preservation of sleep architecture including adequate periods of REM sleep. Dyssomnias are often characterized by the disruption of normal sleep architecture and the loss of REM sleep. Cortical acetylcholine has been reported to be greatest during waking times and during REM sleep (Vazquez J, Am J Physiol. Regul. Integr. Comp. Physiol. 2001 February; 280(2):R598-601). This suggests that chronic sleep disorders characterized by disrupted sleep architecture including reduced and/or fragmented sleep may be amenable to treatment by drugs that increase CNS levels of acetylcholine.
Galantamine has been described for the treatment of sleep-disordered breathing such as snoring and apnea in WO-97/22339).
Galantamine has been used extensively as a curare reversal agent in anesthetic practice in Eastern bloc countries (cf. review by Paskow, 1986) and also experimentally in the West (cf. Bretagne and Valetta, 1965: Wislicki, 1967; Consanitis, 1971).
Galantamine has been marketed by Waldheim (Sanochemia Gruppe) as Nivalin™ in Germany and Austria since the 1970s for indications such as facial neuralgia.
The use of galantamine or an analogue or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for treating Alzheimer's Dementia (AD) and related dementias has been described in EP-0,236,684 (U.S. Pat. No. 4,663,318). This patent only has a generic disclosure of possible dosage forms of galantamine.
U.S. Pat. No. 5,585,375 claims galantamine for treatment of jet lag, when administered in an alertness-increasing amount.
The use of galantamine for treating alcoholism and the administration via a transdermal therapeutic system (TTS) or patch is disclosed in EP-0,449,247 and WO-94/16707. Similarly, the use of galantamine in the treatment of nicotine dependence using administration via a transdermal therapeutic system (TTS) or patch is disclosed in WO-94/16708. Treatment of nerve gas poisoning is disclosed in DE-4,342,174.
A number of applications by E. Snorrason disclose the use of galantamine, analogues thereof and pharmaceutically acceptable salts thereof for the preparation of medicaments for treating mania (U.S. Pat. No. 5,336,675), chronic fatigue syndrome (CFS) (EP-0,515,302; U.S. Pat. No. 5,312,817), the negative effects of benzodiazepine treatment (EP-0,515,301) and the treatment of schizophrenia (U.S. Pat. No. 5,633,238). In these applications and patents, e.g. in U.S. Pat. No. 5,312,817, a number of immediate release tablet formulations of galantamine hydrobromide are given.
WO-97/47304 discloses fast-dissolving or immediate release tablets of galantamine prepared by direct compression. These and other art-known immediate release tablets are administered twice (b.i.d.) or thrice (t.i.d.) daily with an interval of 8 hours. The plasma levels of the active ingredient typically raise sharply (early Tmax and relatively high Cmax) and decline rapidly (deep trough after about 6 to 8 hours).